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J. Biol. Chem., Vol. 281, Issue 2, 951-961, January 13, 2006

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Cross-species Vascular Endothelial Growth Factor (VEGF)-blocking Antibodies Completely Inhibit the Growth of Human Tumor Xenografts and Measure the Contribution of Stromal VEGF^*

Wei-Ching Liang1, Xiumin Wu1, Franklin V. Peale¶, Chingwei V. Lee, Y. Gloria Meng||, Johnny Gutierrez||, Ling Fu¶, Ajay K. Malik2, Hans-Peter Gerber, Napoleone Ferrara3, and Germaine Fuh4

From the Departments of Protein Engineering, Molecular Oncology, ^¶Pathology, and ^||Assay and Automation Technology, Genentech Inc., South San Francisco, California 94080

To fully assess the role of VEGF-A in tumor angiogenesis, antibodies that can block all sources of vascular endothelial growth factor (VEGF) are desired. Selectively targeting tumor-derived VEGF overlooks the contribution of host stromal VEGF. Other strategies, such as targeting VEGF receptors directly or using receptor decoys, result in inhibiting not only VEGF-A but also VEGF homologues (e.g. placental growth factor, VEGF-B, and VEGF-C), which may play a role in angiogenesis. Here we report the identification of novel anti-VEGF antibodies, B20 and G6, from synthetic antibody phage libraries, which block both human and murine VEGF action in vitro. Their affinity-improved variants completely inhibit three human tumor xenografts in mice of skeletal muscle, colorectal, and pancreatic origins (A673, HM-7, and HPAC). Avastin, which only inhibits the tumor-derived human VEGF, is 90% effective at inhibiting HM-7 and A673 growth but is <50% effective at inhibiting HPAC growth. Indeed, HPAC tumors contain more host stroma invasion and stroma-derived VEGF than other tumors. Thus, the functional contribution of stromal VEGF varies greatly among tumors, and systemic blockade of both tumor and stroma-derived VEGF is sufficient for inhibiting the growth of tumor xenografts.

Received for publication, July 27, 2005 , and in revised form, November 1, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Fig. 1 and Table.

¹ Both authors contributed equally to this work.

² Present address: Hollis-Eden Pharmaceutical Inc., San Diego, CA 92121.

³ To whom correspondence may be addressed: Dept. of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080. E-mail: nf{at}gene.com. ⁴ To whom correspondence may be addressed: Dept. of Protein Engineering, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080. E-mail: gml{at}gene.com.

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