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A Fully Human Monoclonal Antibody (CR002) Identifies PDGF-D as a Novel Mediator of Mesangioproliferative Glomerulonephritis

Tammo Ostendorf^*, Claudia R.C. van Roeyen^*, Jeffrey D. Peterson, Uta Kunter^*, Frank Eitner^*, Avin J. Hamad^*, Gerlinde Chan, Xiao-Chi Jia, Jennifer Macaluso, Gadi Gazit-Bornstein, Bruce A. Keyt, Henri S. Lichenstein, William J. LaRochelle and Jürgen Floege^*

*Division Nephrology, University of Aachen, Germany; CuraGen Corporation, Branford, Connecticut; and Abgenix, Inc., Fremont, California

Correspondence to Dr. Jürgen Floege, Division of Nephrology, University Hospital Aachen, Pauwelsstrasse 30, D-52057 Aachen, Germany. Phone: +49-241-8089530; Fax: +49-241-8082446;

ABSTRACT. PDGF-B is of central importance in mesangioproliferative diseases. PDGF-D, a new PDGF isoform, like PDGF-B, signals through the PDGF -receptor. The present study first determined that PDGF-D is mitogenic for rat mesangial cells and is not inhibited by a PDGF-B antagonist. Low levels of PDGF-D mRNA were detected in normal rat glomeruli. After induction of mesangioproliferative nephritis in rats by anti–Thy 1.1 mAb, glomerular PDGF-D mRNA and protein expression increased significantly from days 4 to 9 in comparison with nonnephritic rats. Peak expression of PDGF-D mRNA occurred 2 d later than peak PDGF-B mRNA expression. In addition, PDGF-D serum levels increased significantly in the nephritic animals on day 7. For investigating the functional role of PDGF-D, neutralizing fully human mAb were generated using the XenoMouse technology. Rats with anti–Thy 1.1–induced nephritis were treated on days 3 and 5 with different amounts of a fully human PDGF-DD–specific neutralizing mAb (CR002), equal amounts of irrelevant control mAb, or PBS by intraperitoneal injection. Specific antagonism of PDGF-D led to a dose-dependent (up to 67%) reduction of glomerular cell proliferation. As judged by double immunostaining for 5-bromo-2'-deoxyuridine and -smooth muscle actin, glomerular mesangial cell proliferation was reduced by up to 57%. Reduction of glomerular cell proliferation in the rats that received CR002 was not associated with reduced glomerular expression of PDGF-B mRNA. PDGF-D antagonism also led to reduced glomerular infiltration of monocytes/macrophages (day 5) and reduced accumulation of fibronectin (day 8). In contrast, no effect was noted in normal rats that received an injection of CR002. These data show that PDGF-D is overexpressed in mesangioproliferative states and can act as an auto-, para-, or even endocrine glomerular cell mitogen, indicating that antagonism of PDGF-D may represent a novel therapeutic approach to mesangioproliferative glomerulonephritides. E-mail: juergen.floege@rwth-aachen.de

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673