In vivo evaluation of 177Lu- and 67/64Cu-labeled recombinant fragments of antibody chCE7 for radioimmunotherapy and PET imaging of L1-CAM-positive tumors.

Abstract

PURPOSE:

The L1 cell adhesion protein is overexpressed in tumors, such as neuroblastomas, renal cell carcinomas, ovarian carcinomas, and endometrial carcinomas, and represents a target for tumor diagnosis and therapy with anti-L1-CAM antibody chCE7. Divalent fragments of this internalizing antibody labeled with 67/64Cu and 177Lu were evaluated to establish a chCE7 antibody fragment for radioimmunotherapy and positron emission tomography imaging, which combines high-yield production with improved clearance and biodistribution properties.

EXPERIMENTAL DESIGN:

chCE7F(ab')2 fragments were produced in high amounts (0.2 g/L) in HEK-293 cells, substituted with the peptide-linked tetraazamacrocycle 3-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate-triglycyl-L-p-isothiocyanato-phenylalanine, and labeled with 67Cu and 177Lu. In vivo bioevaluation involved measuring kinetics of tumor and tissue uptake in nude mice with SK-N-BE2c xenografts and NanoPET (Oxford Positron Systems, Oxford, United Kingdom) imaging with 64Cu-3-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate-triglycine-chCE7F(ab')2.

RESULTS:

The 177Lu- and 67Cu-labeled immunoconjugates reached maximal tumor accumulation at 24 hours after injection with similar levels of 12%ID/g to 14%ID/g. Blood levels dropped to 1.0%ID/g for the 177Lu fragment and 2.3%ID/g for the 67Cu fragment at 24 hours. The most striking difference concerned radioactivity present in the kidneys, being 34.5%ID/g for the 177Lu fragment and 16.0%ID/g for the 67Cu fragment at 24 hours. Positron emission tomography imaging allowed clear visualization of s.c. xenografts and peritoneal metastases and a detailed assessment of whole-body tracer distribution.

CONCLUSIONS:

67/64Cu- and 177Lu-labeled recombinant chCE7F(ab')2 revealed suitable in vivo characteristics for tumor imaging and therapy but displayed higher kidney uptake than the intact monoclonal antibody. The 67Cu- and 177Lu-labeled immunoconjugates showed different in vivo behavior, with 67/64Cu-3-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate-triglycine-F(ab')2 appearing as the more favorable conjugate due to superior tumor/kidney ratios.

• Authors: Jürgen Grünberg, Ilse Novak-Hofer, Michael Honer, Kurt Zimmermann, Karin Knogler, Peter Bläuenstein, Simon Ametamey, Helmut R Maecke, P August Schubiger
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 14 Pg. 5112-20 (Jul 15 2005) ISSN: 1078-0432 [Print] United States
• PMID: 16033825 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Copper Radioisotopes
• Immunoconjugates
• Immunoglobulin Fragments
• Neural Cell Adhesion Molecule L1
• Radioisotopes
• Lutetium

Topics

• Animals
• Copper Radioisotopes
• Humans
• Immunoconjugates
• Immunoglobulin Fragments
• Lutetium
• Mice
• Mice, Nude
• Neoplasms (diagnostic imaging)
• Neural Cell Adhesion Molecule L1 (chemistry, immunology, pharmacokinetics)
• Neuroblastoma (pathology)
• Positron-Emission Tomography (methods)
• Radioisotopes
• Tissue Distribution
• Transplantation, Heterologous
• Tumor Cells, Cultured