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[Cancer Research 62, 867-874, February 1, 2002]
© 2002 American Association for Cancer Research

Tumor Biology

Differential Binding of Drugs Containing the NGR Motif to CD13 Isoforms in Tumor Vessels, Epithelia, and Myeloid Cells1

Flavio Curnis, Gianluigi Arrigoni, Angelina Sacchi, Lucia Fischetti, Wadih Arap, Renata Pasqualini and Angelo Corti2

Department of Pathology and Molecular Medicine, DIBIT-San Raffaele H Scientific Institute, 20132 Milan, Italy [F. C., G. A., A. S., L. F., A. C.], and M. D. Anderson Cancer Center, Houston, Texas 77030 [W. A., R. P.]

The NGR peptide motif is an aminopeptidase N (CD13) ligand that targets angiogenic blood vessels. NGR-containing peptides have proven useful for delivering cytotoxic drugs, proapoptotic peptides, and tumor necrosis factor-{alpha} (TNF) to tumor vasculature. Given that CD13 is not only expressed in the angiogenic endothelium but also in other cell types, the mechanism(s) for the tumor-homing properties of NGR-drug conjugates remains elusive. We have examined the expression of CD13 in normal and neoplastic human tissues and cells by using two anti-CD13 monoclonal antibodies. The immunoreactivity patterns obtained with cultured cells and tissue sections from kidney, breast, and prostate carcinomas suggest that different CD13 forms are expressed in myeloid cells, epithelia, and tumor-associated blood vessels. Both, direct binding assays with a CNGRCG-TNF conjugate (NGR-TNF) and competitive inhibition experiments with anti-CD13 antibodies showed that a CD13 isoform expressed in tumor blood vessels could function as a vascular receptor for the NGR motif. In contrast, CD13 expressed in normal kidney and in myeloid cells failed to bind to NGR-TNF. Consistently with these results, neither murine125I-NGR-TNF nor 125I-TNF accumulated in normal organs containing CD13-expressing cells after administration to mice. These findings may explain the selectivity and the tumor-homing properties of NGR-drug conjugates and may have important implications in the development of vascular-targeted therapies based on the NGR/CD13 system.




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Copyright © 2002 by the American Association for Cancer Research.