This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grünberg, J. Articles by Schubiger, P. A. Search for Related Content PubMed PubMed Citation Articles by Grünberg, J. Articles by Schubiger, P. A.

In vivo Evaluation of ¹⁷⁷Lu- and ^67/64Cu-Labeled Recombinant Fragments of Antibody chCE7 for Radioimmunotherapy and PET Imaging of L1-CAM-Positive Tumors

Authors' Affiliations: ¹ Center for Radiopharmaceutical Science ETH-PSI-USZ, Paul Scherrer Institute, Villigen, Switzerland and ² Division of Radiological Chemistry, University Hospital Basel, Basel, Switzerland

Requests for reprints: Ilse Novak-Hofer, Center for Radiopharmaceutical Science ETH-PSI-USZ, Paul Scherrer Institute, CH-5232 Villigen, Switzerland. Phone: 41-56-310-4067; Fax: 41-56-310-2849; E-mail: ilse.novak{at}psi.ch.

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.

This article has been cited by other articles:

				S. D. Voss, S. V. Smith, N. DiBartolo, L. J. McIntosh, E. M. Cyr, A. A. Bonab, J. L. J. Dearling, E. A. Carter, A. J. Fischman, S. T. Treves, et al. Positron emission tomography (PET) imaging of neuroblastoma and melanoma with 64Cu-SarAr immunoconjugates PNAS, October 30, 2007; 104(44): 17489 - 17493. [Abstract] [Full Text] [PDF]

				R. M. Sharkey, H. Karacay, W. J. McBride, E. A. Rossi, C.-H. Chang, and D. M. Goldenberg Bispecific Antibody Pretargeting of Radionuclides for Immuno Single-Photon Emission Computed Tomography and Immuno Positron Emission Tomography Molecular Imaging: An Update Clin. Cancer Res., September 15, 2007; 13(18): 5577s - 5585s. [Abstract] [Full Text] [PDF]

				K. Knogler, J. Grunberg, K. Zimmermann, S. Cohrs, M. Honer, S. Ametamey, P. Altevogt, M. Fogel, P. A. Schubiger, and I. Novak-Hofer Copper-67 Radioimmunotherapy and Growth Inhibition by Anti-L1-Cell Adhesion Molecule Monoclonal Antibodies in a Therapy Model of Ovarian Cancer Metastasis Clin. Cancer Res., January 15, 2007; 13(2): 603 - 611. [Abstract] [Full Text] [PDF]