Evaluation of anti-podoplanin rat monoclonal antibody NZ-1 for targeting malignant gliomas.

Abstract

INTRODUCTION:

Podoplanin/aggrus is a mucin-like sialoglycoprotein that is highly expressed in malignant gliomas. Podoplanin has been reported to be a novel marker to enrich tumor-initiating cells, which are thought to resist conventional therapies and to be responsible for cancer relapse. The purpose of this study was to determine whether an anti-podoplanin antibody is suitable to target radionuclides to malignant gliomas.

METHODS:

The binding affinity of an anti-podoplanin antibody, NZ-1 (rat IgG(2a)), was determined by surface plasmon resonance and Scatchard analysis. NZ-1 was radioiodinated with (125)I using Iodogen [(125)I-NZ-1(Iodogen)] or N-succinimidyl 4-guanidinomethyl 3-[(131)I]iodobenzoate ([(131)I]SGMIB-NZ-1), and paired-label internalization assays of NZ-1 were performed. The tissue distribution of (125)I-NZ-1(Iodogen) and that of [(131)I]SGMIB-NZ-1 were then compared in athymic mice bearing glioblastoma xenografts.

RESULTS:

The dissociation constant (K(D)) of NZ-1 was determined to be 1.2 × 10(-10) M by surface plasmon resonance and 9.8 × 10(-10) M for D397MG glioblastoma cells by Scatchard analysis. Paired-label internalization assays in LN319 glioblastoma cells indicated that [(131)I]SGMIB-NZ-1 resulted in higher intracellular retention of radioactivity (26.3 ± 0.8% of initially bound radioactivity at 8 h) compared to that from the (125)I-NZ-1(Iodogen) (10.0 ± 0.1% of initially bound radioactivity at 8 h). Likewise, tumor uptake of [(131)I]SGMIB-NZ-1 (39.9 ± 8.8 %ID/g at 24 h) in athymic mice bearing D2159MG xenografts in vivo was significantly higher than that of (125)I-NZ-1(Iodogen) (29.7 ± 6.1 %ID/g at 24 h).

CONCLUSIONS:

The overall results suggest that an anti-podoplanin antibody NZ-1 warrants further evaluation for antibody-based therapy against glioblastoma.

• Authors: Yukinari Kato, Ganesan Vaidyanathan, Mika Kato Kaneko, Kazuhiko Mishima, Nidhi Srivastava, Vidyalakshmi Chandramohan, Charles Pegram, Stephen T Keir, Chien-Tsun Kuan, Darell D Bigner, Michael R Zalutsky
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 37 Issue 7 Pg. 785-94 (Oct 2010) ISSN: 1872-9614 [Electronic] United States
• PMID: 20870153 (Publication Type: Evaluation Study, Journal Article)
• Copyright: Copyright © 2010 Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Anti-Idiotypic
• Antibodies, Monoclonal
• Iodine Radioisotopes
• Membrane Glycoproteins
• Pdpn protein, rat
• Radiopharmaceuticals

Topics

• Animals
• Antibodies, Anti-Idiotypic (therapeutic use)
• Antibodies, Monoclonal (immunology)
• Brain Neoplasms (immunology, pathology, therapy)
• Cell Line, Tumor
• Female
• Flow Cytometry
• Glioblastoma (immunology, pathology, therapy)
• Iodine Radioisotopes (pharmacokinetics)
• Membrane Glycoproteins (antagonists & inhibitors, immunology)
• Mice
• Mice, Inbred BALB C
• Radioimmunotherapy
• Radiopharmaceuticals (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Surface Plasmon Resonance
• Tissue Distribution